Major worldwide study clusters long COVID symptoms into 3 groups

Healthcare systems around the world facing the challenge of diagnosing long COVID might benefit by separating the symptoms of the disease into three general clusters: persistent fatigue with bodily pain or mood swings, cognitive problems and ongoing respiratory problems that persist at least three months after acute infection.

That’s what hundreds of expert authors known as the Global Burden of Disease Long COVID Collaborators did in a Bayesian meta-regression analysis published Monday in JAMA Network.

The three-month cutoff comes from the World Health Organization (WHO) saying that’s how long somebody should have symptoms before being diagnosed with long COVID, aka post-COVID-19 condition. The clusters expand on three key symptoms that a WHO consensus exercise focused on—fatigue, memory loss and shortness of breath.

“We noticed in published studies and 10 cohort studies we could examine in greater detail with their researchers that these are the most common symptoms,” the JAMA Network’s study corresponding author Theo Vos, Ph.D., tells Fierce Healthcare. “We also wanted to quantify the relative severity of long COVID using disability weights derived for our ongoing work on the Global Burden of Disease study.”

The disability weights are numbered between 0 and 1 and indicate the amount of health lost by people experiencing a particular state of health.

“One health state that we have been using for post-infection malaise after dengue and Ebola is based on a description of fatigue, bodily pain and mood swings,” says Vos, who works at the Institute for Health Metrics and Evaluation at the University of Washington. “Hence, we decided to make those symptoms one cluster.”

Vos and co-authors found that 6.2% of the 1.2 million patients from 22 countries who exhibited COVID-19 symptoms in 2020 and 2021 experienced long COVID. The data come from 54 studies and two medical databases. The long COVID data come from individuals infected with the delta variant, rather than omicron.

“Quantifying the number of individuals with long COVID may help policymakers ensure adequate access to services to guide people toward recovery, return to the workplace or school, and restore their mental health and social life,” the study states.

The diagnostic advantages in approaching long COVID the way that the researchers in the JAMA Network study do “has major advantages over simply listing counts of symptoms as most publications tend to do,” says Vos. “Also, importantly, we looked at the difference between people who had COVID-19 versus those who did not—and, where available, information from patients on how they were before COVID-19, to better define what can be attributed as long COVID.”

Many of the symptoms of long COVID also occur frequently in people who have not had COVID-19.

“By approaching long COVID like we approach all diseases in the Global Burden of Disease [study], we can make statements about the average severity of long COVID (similar values to people with long-term consequences of moderate to severe traumatic brain injury or people who are deaf) and comparing the magnitude of health loss from long COVID to other diseases.”

Compared to all other diseases causing health loss in 2021, COVID-19 ranked higher than dementia or osteoarthritis of the knee and just below schizophrenia and COPD.

“This is an estimate that is not yet published but will be part of the upcoming release of [Global Burden of Disease] 2021,” Vos says.

In the JAMA Network study, too few individuals with asymptomatic COVID-19 later complained of long COVID symptoms, according to the data, and for that reason researchers excluded them from the analysis. They cautioned, however, that “if Long COVID symptoms do occur in those who have an asymptomatic SARS-CoV-2 infection, the estimates would be higher.”

Researchers found that women who needed to be hospitalized for initial SARS-CoV-2 infection faced the greatest risk of long COVID, especially if they were treated in intensive care units.

That means “the pattern of long COVID symptoms by sex is distinct from that of severe acute SARS-CoV-2 infection, which tends to affect more males,” the study states. This might suggest a difference in the “underlying mechanism” for long COVID and the severity of initial infection.  

Vos explains: “Most of the effects of acute SARS-CoV-2 infection can be directly attributed to the virus. While there is a hypothesis that long COVID could be caused by lingering virus in the body, a more likely explanation is that the virus triggered an overshooting of the immune system for reasons we still do not fully understand.”

The researchers note that women aren’t as adversely affected by viral infections and exhibit higher antibody responses than men. But women are more likely to have adverse reactions to vaccinations and antiviral drugs. The study states that “X chromosome-linked genes are thought to influence susceptibility to viral infections as well as autoimmune diseases, lending support to autoimmune processes playing a role in the development of long COVID. 

A prolonged state of low-grade infection with a hyperimmune response, coagulation or vasculopathy, endocrine and autonomic dysregulation, and a maladaptation of the angiotensin-converting enzyme 2 pathway have been postulated as the underlying pathophysiology of long COVID.”

These responses might be compounded by the immobilization resulting during extended hospital stays.

Vos says that “women are twice more likely than men to develop long COVID, [which] mirrors a similar sex ratio we see for many autoimmune diseases such as rheumatoid arthritis or thyroid problems.”